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Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4)

Roland Buhl, François Maltais, Roger Abrahams, Leif Bjermer, Eric Derom, Gary Ferguson, Matjaž Fležar, Jacques Hébert, Lorcan McGarvey, Emilio Pizzichini, Jim Reid, Antony Veale, Lars Grönke, Alan Hamilton, Lawrence Korducki, Kay Tetzlaff, Stella Waitere-Wijker, Henrik Watz, Eric Bateman
European Respiratory Journal 2015 45: 969-979; DOI: 10.1183/09031936.00136014
Roland Buhl
1Pulmonary Department, Mainz University Hospital, Mainz, Germany
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  • For correspondence: r.buhl@3-med.klinik.uni-mainz.de
François Maltais
2Département de Médecine, Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada
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Roger Abrahams
3Department of Clinical Research, Morgantown Pulmonary Associates, Morgantown, WV, USA
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Leif Bjermer
4Department of Respiratory Medicine and Allergology, Lund University, Lund, Sweden
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Eric Derom
5Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
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Gary Ferguson
6Pulmonary Research Institute of Southeast Michigan, Livonia, MI, USA
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Matjaž Fležar
7Klinika Golnik, Golnik, Slovenia
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Jacques Hébert
8Department of Medicine, Centre de Recherche Appliquée en Allergie de Québec (CRAAQ), Québec, Canada
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Lorcan McGarvey
9Department of Medicine, Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
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Emilio Pizzichini
10Department of Pulmonology, NUPAIVA (Asthma Research Centre), Universidade Federal de Santa Catarina, Santa Catarina, Brazil
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Jim Reid
11Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
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Antony Veale
12Department of Respiratory Medicine, The Queen Elizabeth Hospital, Adelaide, Australia
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Lars Grönke
13Department of Medical Affairs Respiratory, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
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Alan Hamilton
14Medical Department, Boehringer Ingelheim, Burlington, Ontario, Canada
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Lawrence Korducki
15Department of Biostatistics, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA
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Kay Tetzlaff
13Department of Medical Affairs Respiratory, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
16Department of Sports Medicine, Medical Clinic V, University of Tübingen, Tübingen, Germany
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Stella Waitere-Wijker
17Medical Department, Boehringer Ingelheim B.V., Alkmaar, The Netherlands
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Henrik Watz
18Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North, Member of the German Center for Lung Research, Grosshansdorf, Germany
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Eric Bateman
19Division of Pulmonology, Department of Medicine, University of Cape Town Lung Institute, Cape Town, South Africa
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  • Author Correction - June 01, 2015

Abstract

Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials.

Patients received tiotropium+olodaterol FDC 2.5/5 μg or 5/5 μg, tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg delivered once-daily via Respimat inhaler over 52 weeks. Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0–3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks.

In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment. Both FDCs significantly improved FEV1 AUC0–3 and trough FEV1 response versus the mono-components in both studies. Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 μg. Incidence of adverse events was comparable between the FDCs and the mono-components.

These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD.

Abstract

Lung function/symptomatic benefits of daily tiotropium+olodaterol fixed-dose combination in moderate-very severe COPD http://ow.ly/DIKiY

Introduction

Long-acting bronchodilators, such as long-acting muscarinic antagonists (LAMAs), are the cornerstone of maintenance therapy for patients with moderate to very severe chronic obstructive pulmonary disease (COPD) whose symptoms are not adequately controlled by short-acting bronchodilators alone [1, 2].

Tiotropium is an established once-daily LAMA that improves the main functional and patient-orientated outcomes of COPD [3–8]. Tiotropium has also been demonstrated to moderate disease progression, even in the early stages of COPD (e.g. patients not receiving maintenance therapy [9] or those with Global initiative for chronic Obstructive Lung Disease (GOLD) stage 2 disease [10]).

The novel once-daily long-acting β2-agonist (LABA) olodaterol is a highly selective and nearly full β2 agonist [11, 12] that provides 24-h bronchodilation in patients with COPD [13–16]. Olodaterol is also associated with symptomatic benefit [17] and enhanced exercise capacity [18].

An option recommended by GOLD for patients not adequately controlled on a single long-acting bronchodilator is to combine a LAMA with a LABA [2]. This has prompted the development of combining LAMA+LABA as fixed-dose combinations (FDCs) [1]. The complementary modes of action of tiotropium and olodaterol have previously been demonstrated in animal models and phase II clinical trials [19–22].

We hypothesised that combination therapy with tiotropium+olodaterol FDC would provide improvements in lung function, health-related quality of life and other COPD disease parameters compared to monotherapy with either component alone, with a comparable safety profile. These two replicate, global, phase III trials (TOnado 1 and 2) aimed to assess the efficacy and safety of once-daily treatment with orally inhaled tiotropium+olodaterol FDC 5/5 µg or 2.5/5 µg delivered via the Respimat Soft Mist Inhaler (Boehringer Ingelheim, Ingelheim am Rhein, Germany) compared with their individual mono-components in patients with moderate to very severe COPD (GOLD stage 2–4) over 52 weeks.

Methods

Study design

These were multinational, replicate, phase III, multicentre, randomised, double-blind, active-controlled, five-arm, parallel-group studies, registered with ClinicalTrials.gov (Study 1237.5: NCT01431274; Study 1237.6: NCT01431287) (fig. 1). Three primary end points were evaluated after 24 weeks of treatment: forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0–3) response (in each individual trial), trough FEV1 response in each individual trial (response defined as change from baseline; mean of the values of 1 h and 10 min prior to the first dose of study medication); and St George's Respiratory Questionnaire (SGRQ) total score (SGRQ was analysed in a pre-specified combined analysis of data from both studies). Pulmonary function tests (PFTs) were performed on day 1 and at weeks 2, 6, 12, 18, 24, 32, 40 and 52. SGRQ was completed on day 1 and after 12, 24 and 52 weeks, prior to PFTs and all other procedures. Details of the study design, assessments performed and statistical methodology are provided in table S1 of the online supplementary material.

FIGURE 1
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FIGURE 1

Study design (Study 1237.5: NCT01431274; Study 1237.6: NCT0143 1287). R: randomisation; FDC: fixed- dose combination. #: primary end-point assessment.

Patients continued to receive treatment with inhaled corticosteroids as required and were provided with salbutamol/albuterol metered-dose inhaler (100 μg per actuation) as rescue medication to be used as necessary at any point during the trial. Temporary increases in the dose or addition of oral steroids or theophylline preparations were allowed during the treatment portion of the study; PFTs were not performed within 7 days of the last administered dose.

Patients

Patients were randomised if they met the following main inclusion criteria: outpatients aged ≥40 years with a history of moderate to very severe COPD (GOLD stage 2–4) [23]; post-bronchodilator FEV1 <80% of predicted normal; post-bronchodilator FEV1/forced vital capacity (FVC) <70%; current or ex-smokers with a smoking history of >10 pack–years.

Patients with a significant disease other than COPD were excluded from the trials. Other exclusion criteria included: clinically relevant abnormal baseline laboratory parameters or a history of asthma; myocardial infarction within 1 year of screening; unstable or life-threatening cardiac arrhythmia; known active tuberculosis; clinically evident bronchiectasis; cystic fibrosis or life-threatening pulmonary obstruction; hospitalised for heart failure within the past year; diagnosed thyrotoxicosis or paroxysmal tachycardia; previous thoracotomy with pulmonary resection; regular use of daytime oxygen if patients were unable to abstain during clinic visits; or currently enrolled in a pulmonary rehabilitation programme (or completed in the 6 weeks before screening).

Patients with moderate or severe renal impairment (creatinine clearance ≤50 mL·min−1) were not excluded from the study but were closely monitored by the investigator.

Both studies were performed in accordance with the Declaration of Helsinki, International Conference on Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice and local regulations. The protocols were approved by the authorities and the ethics committees of the respective institutions, and signed informed consent was obtained from all patients.

Results

Patient disposition and baseline characteristics

A total of 5163 patients (2624 Study 1237.5; 2539 Study 1237.6) were randomised to receive treatment in 25 countries; 5162 patients were treated (2624 Study 1237.5; 2538 Study 1237.6). Overall, 84.6% of patients (86.2% Study 1237.5; 83.0% Study 1237.6) completed the studies. The discontinuation rate was higher in the monotherapy than the combination treatment groups in both studies (fig. 2). The data for the individual studies are presented in the online supplementary material.

FIGURE 2
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FIGURE 2

Patient disposition and flow in (a) Study 1237.5 and (b) Study 1237.6. Tio: tiotropium; Olo: olodaterol; FDC: fixed-dose combination. #: not due to adverse event.

Baseline demographics were generally similar across treatment groups. The majority of patients were male (72.9% total) and approximately one-third were current smokers. Most patients were classified as GOLD stage 2/3 (88.6%); the remaining patients (11.3%) were classified as GOLD stage 4. Overall, 86.4% of patients had diagnosed co-morbidities at baseline; 1107 (21.4%) had cardiac disorders and 2481 (48.1%) had vascular disorders including hypertension (table 1, and table S2 in the online supplementary material for individual study data).

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TABLE 1

Demographic and baseline patient characteristics (treated population): combined data (n=5162)

Efficacy

Lung function

FEV1 AUC0–3 responses for tiotropium+olodaterol FDC 2.5/5 μg, 5/5 μg, tiotropium 2.5 μg, 5 μg and olodaterol 5 μg were 241, 256, 148, 139 and 133 mL, respectively, in Study 1237.5, and 256, 268, 125, 165 and 136 mL, respectively, in Study 1237.6. Improvements in adjusted mean FEV1 AUC0–3 with tiotropium+olodaterol FDC 5/5 µg and 2.5/5 µg over the corresponding individual components in the individual studies and the combined analysis were statistically significant (p<0.0001 for all comparisons) (table 2, and table S3 in the online supplementary material). The comparison of tiotropium+olodaterol FDC 2.5/5 μg with tiotropium 5 μg (performed to compare the combination with the licensed tiotropium dose) was p<0.0001 for all analyses.

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TABLE 2

FEV1 AUC0–3 and trough FEV1 responses (i.e. change from baseline) after 24 weeks of treatment (full analysis set) in Studies 1237.5 and 1237.6 separately

Trough FEV1 responses after 24 weeks for tiotropium+olodaterol FDC 2.5/5 μg, 5/5 μg, tiotropium 2.5 μg, 5 μg and olodaterol 5 μg were 111, 136, 83, 65 and 54 mL, respectively, in Study 1237.5, and 125, 145, 62, 96 and 57 mL, respectively, in Study 1237.6. Improvements in the adjusted mean trough FEV1 with tiotropium+olodaterol FDC 5/5 µg and 2.5/5 µg over the corresponding individual components in both the individual studies and the combined data were statistically significant (p<0.05 for all comparisons) (table 2, and table S3 in the online supplementary material).

There was no influence of sex on either FEV1 AUC0–3 or trough FEV1 response. An analysis of FEV1 AUC0–3 and trough FEV1 response according to baseline disease severity showed that responses were lower in patients with more severe disease (table S4 in the online supplementary material).

An analysis of FEV1 AUC0–3 and trough FEV1 according to inhaled corticosteroid use is presented in table 3. This confirms that tiotropium+olodaterol improves lung function whether patients were receiving inhaled corticosteroid or not.

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TABLE 3

FEV1 AUC0–3 and trough FEV1 responses (i.e. change from baseline) after 24 weeks of treatment by ICS usage (full analysis set, combined data)

Improvements were observed for FEV1 values on all test days over each of the 52-week studies (fig. 3a and b, and fig. S1 in the online supplementary material). Responses in trough FVC and FVC AUC0–3 over 24 weeks of treatment were in line with the primary end points (table S5 in the online supplementary material).

FIGURE 3
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FIGURE 3

Lung function end points (combined data set) over 52 weeks: full analysis set. a) adjusted mean trough forced expiratory volume in 1 s (FEV1); all comparisons of Tio+Olo 5/5 μg and 2.5/5 μg versus the monotherapies were statistically significant (p<0.001). b) FEV1 area under the curve from 0 to 3 h (AUC0–3); all comparisons of Tio+Olo 5/5 μg and 2.5/5 μg versus the monotherapies were statistically significant (p<0.01). Tio: tiotropium; Olo: olodaterol.

Health status and symptomatic benefit

After 24 weeks, the pre-specified analysis of the adjusted mean SGRQ total score (table 4) revealed statistically significant improvements for tiotropium+olodaterol FDC 5/5 µg over corresponding individual components (versus olodaterol 5 µg: −1.693 (0.553), p<0.01; versus tiotropium 5 µg: −1.233 (0.551), p<0.05) but not for tiotropium+olodaterol FDC 2.5/5 µg versus the individual components (table 5).

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TABLE 4

St George's Respiratory Questionnaire (SGRQ) score at 24 weeks (full analysis set)

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TABLE 5

St George's Respiratory Questionnaire (SGRQ) score at 24 weeks (full analysis set): treatment comparisons

Responder rates for SGRQ total scores after 24 weeks for the combined data set (responders defined as decrease in SGRQ total score ≥4.0 units, minimum clinically important difference) were: tiotropium+olodaterol FDC 5/5 µg, 57.5%; tiotropium+olodaterol FDC 2.5/5 µg, 53.2%, and responder rates of 49.6%, 48.7% and 44.8% for tiotropium 2.5 µg, 5 µg and olodaterol 5 µg, respectively. The increases in responder rate for tiotropium+olodaterol FDC 5/5 µg over its individual components were statistically significant (nominal p<0.05), and for tiotropium+olodaterol FDC 2.5/5 µg there was a significant improvement in responder rate versus olodaterol 5 µg and tiotropium 5 µg but not tiotropium 2.5 µg (table 5).

The pre-specified analysis of the key secondary end point (Mahler Transition Dyspnoea Index focal score at 24 weeks (combined data set)) showed statistically significant improvements for both tiotropium+olodaterol FDCs versus their mono-components (nominal p<0.05) (table S6 in the online supplementary material).

Rescue medication

Both tiotropium+olodaterol FDC 5/5 µg and 2.5/5 µg provided reductions in adjusted weekly mean daily (24-h) rescue medication use compared to the monotherapy components throughout the 52-week treatment period (fig. S2 in the online supplementary material).

Exacerbations

Figure S3 in the online supplementary material shows Kaplan–Meier estimates of probability of moderate/severe COPD exacerbation. There was a trend for improvement in exacerbations with both FDCs versus the monotherapy components.

Safety

Table 6 shows a summary of adverse events for the combined data set (for Studies 1237.5 and 1237.6, see table S7 in the online supplementary material). Adverse event incidence was generally balanced across all treatment groups, with the majority being mild to moderate in severity. The proportion of patients who reported at least one adverse event while on treatment was 74.4%. Overall, 6.4% of patients experienced adverse events that were deemed treatment related; rates of serious adverse events were broadly similar across treatment arms. Rates of serious adverse events were 16.4%, with fatality rates of 1.5%. The majority of treatment-emergent adverse events (incidence of >3%) were respiratory events, in particular COPD exacerbations and infections according to Medical Dictionary for Regulatory Activities (MedDRA) classifications. A higher proportion of patients in the tiotropium+olodaterol FDC 2.5/5 µg arm experienced upper respiratory infections while on treatment compared with the other arms. Respiratory events (including COPD exacerbations) were more frequent among patients treated with monotherapies. No significant abnormalities in vital signs or laboratory parameters were observed in either study.

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TABLE 6

Summary of adverse events: combined analysis (treated set)

Overall incidence of adverse events in the subset of patients with cardiac history was broadly comparable (78.1%, 75.8%, 79.0%, 80.6% and 79.7% in the tiotropium+olodaterol FDC 5/5 µg, tiotropium+olodaterol FDC 2.5/5 µg, tiotropium 2.5 µg, 5 µg and olodaterol 5 µg groups, respectively). Rate ratios for major adverse cardiac events (MACE) and “cardiac disorders” System Organ Class (SOC) are presented in table S8 of the online supplementary material, which demonstrates that the incidences of these events were similar with the FDCs and individual components.

Discussion

This pair of replicate, 52-week studies of the effects of once-daily combination of tiotropium+olodaterol administered via the Respimat Soft Mist Inhaler in patients with moderate to very severe COPD confirm statistically significant increases for the primary lung-function end points of trough FEV1 and FEV1 AUC0–3 response after 24 weeks versus either tiotropium or olodaterol alone. These results are supported by a range of secondary lung-function end points over 52 weeks. FEV1 AUC0–3 and trough FEV1 reflect bronchodilator benefit at the beginning and end of a 24-h cycle and are important measures in the selection of optimum doses and dosing frequency.

Long-acting bronchodilators remain the cornerstone of COPD maintenance therapy [2]. However, the combination of bronchodilators with different modes of action has not been commonly prescribed in clinical practice [1] due, in part, to the lack, until recently, of available FDCs of LAMA+LABA. Olodaterol is a novel once-daily LABA that has been designed as a combination partner for tiotropium, with matching pharmacokinetic and pharmacodynamic profiles [11]. Initial results have indicated that olodaterol may augment the beneficial effects of tiotropium in patients with COPD [21, 22].

The results of our trial are broadly similar with those reported for other LAMA+LABA FDCs [24–26]. However, comparisons between trials are inadvisable owing to differences in study design, including duration and patient population. Compared with those performed with indacaterol/glycopyrronium [24, 25], our studies included a higher proportion of patients with severe or very severe COPD; the fact that, in general, patients with lower lung function show smaller responses to treatment in clinical trials may explain why the increases with dual bronchodilator treatment were slightly lower. An earlier study with the FDC of tiotropium+olodaterol that included fewer patients with very severe disease showed larger effect sizes than the current studies [27].

Symptomatic benefit of the FDC was demonstrated by statistically significant improvements in mean SGRQ total score; compared with monotherapy, this was observed with tiotropium+olodaterol FDC 5/5 μg but not with 2.5/5 μg. Improvements in SGRQ that exceeded the minimum clinically important difference of 4 units for this measure were seen in all treatment arms, but the difference between the FDCs and the monotherapies did not meet this threshold [28]. Since there was no placebo arm, further analysis of the relevance of these improvements is limited. Responder analyses have been proposed as an additional approach to assessing efficacy of treatments in COPD, particularly for studies in which second and third treatments are added to current therapy [28]. In our studies, responder rates, defined as a reduction in SGRQ total score of ≥4 units from baseline, were significantly greater for tiotropium+olodaterol FDC 5/5 μg compared with its monotherapy components and for 2.5/5 µg compared with olodaterol 5 µg.

The doses of tiotropium and olodaterol used in these studies were based on previously published dose–response studies of this drug combination [21, 22]. In the latter, although a dose response for lung function was observed with increasing doses of tiotropium added to a fixed dose of olodaterol, the increase with tiotropium 2.5 µg when added to olodaterol was smaller than the increase with 5 µg when added to olodaterol [21, 22]. Overall, based on the results of the current studies and TIOSPIR, the optimum dose of tiotropium is considered to be 5 µg, both as monotherapy and in combination with olodaterol.

The assessment of safety in our studies yielded no specific concerns in spite of the inclusion of a relatively large proportion of patients with GOLD stage 4 disease and a substantial proportion with co-morbidities. The number of adverse events in the arms with tiotropium+olodaterol FDCs were not higher than in those receiving the individual components; there was also no difference in incidence of adverse events with the higher and lower doses of tiotropium.

“Dry mouth” (typically associated with LAMAs) was reported as a side effect in <2% of patients, possibly attributable to the fact that the majority of patients included in these trials had previously received tiotropium. Additionally, there appears to be no increase in risk of experiencing either a MedDRA SOC “cardiac” or MACE with tiotropium+olodaterol FDC versus the mono-components, and no imbalances between treatment groups were seen in the subgroup of patients with a history of cardiac disease.

Our studies have several limitations. Firstly, there was no placebo group; it was considered inappropriate to deny patients with symptomatic COPD the use of even one long-acting bronchodilator in a study lasting 1 year. Furthermore, these studies were not designed to assess the impact of tiotropium+olodaterol on COPD exacerbations. However, the limited exacerbation data from these studies are encouraging and in line with results for other LAMA+LABA combinations [25]. Further studies powered to examine this end point are planned.

Conclusions

These replicate studies confirm the efficacy and safety of once-daily dosing with tiotropium+olodaterol FDC as maintenance therapy in patients with moderate to very severe COPD (GOLD stage 2–4). The fixed dose of 5 μg of each appears to be optimal in the combination, providing significant improvement in all three primary end points (trough FEV1, FEV1 AUC0–3 and health status) compared to tiotropium or olodaterol administered alone.

Acknowledgements

The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors. They take full responsibility for the scope, direction, content of, and editorial decisions relating to, the manuscript, were involved at all stages of development and have approved the submitted manuscript. The authors received no compensation related to the development of the manuscript.

This work was supported by Boehringer Ingelheim Pharma GmbH & Co. KG. Medical writing assistance was provided by Louise Alder and Rob Kite, on behalf of Complete HealthVizion, and was contracted and compensated by Boehringer Ingelheim Pharma GmbH & Co. KG. The contribution of Holger Huisman (Boehringer Ingelheim B.V., Alkmaar, The Netherlands) is also acknowledged.

Footnotes

  • This version of this article has been amended. The amendment is outlined in the correction published in the June 2015 issue of the European Respiratory Journal [DOI: 10.1183/09031936.50136014].

  • For editorial comments see Eur Respir J 2015; 45: 869–871 [DOI: 10.1183/09031936.00027915]

  • This article has supplementary material available from erj.ersjournals.com

  • Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com

  • ↵Clinical trials: These studies are registered at www.clinicaltrials.gov with identifier numbers NCT01431274 and NCT01431287, and Boehringer Ingelheim study numbers 1237.5 and 1237.6.

  • ↵Support statement: This work was supported by Boehringer Ingelheim Pharma GmbH & Co. KG. Medical writing assistance was contracted and compensated by Boehringer Ingelheim Pharma GmbH & Co. KG.

  • Received July 25, 2014.
  • Accepted October 19, 2014.
  • Copyright ©ERS 2015

ERJ Open articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

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Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4)
Roland Buhl, François Maltais, Roger Abrahams, Leif Bjermer, Eric Derom, Gary Ferguson, Matjaž Fležar, Jacques Hébert, Lorcan McGarvey, Emilio Pizzichini, Jim Reid, Antony Veale, Lars Grönke, Alan Hamilton, Lawrence Korducki, Kay Tetzlaff, Stella Waitere-Wijker, Henrik Watz, Eric Bateman
European Respiratory Journal Apr 2015, 45 (4) 969-979; DOI: 10.1183/09031936.00136014

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Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4)
Roland Buhl, François Maltais, Roger Abrahams, Leif Bjermer, Eric Derom, Gary Ferguson, Matjaž Fležar, Jacques Hébert, Lorcan McGarvey, Emilio Pizzichini, Jim Reid, Antony Veale, Lars Grönke, Alan Hamilton, Lawrence Korducki, Kay Tetzlaff, Stella Waitere-Wijker, Henrik Watz, Eric Bateman
European Respiratory Journal Apr 2015, 45 (4) 969-979; DOI: 10.1183/09031936.00136014
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